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Pivotal role of NOX-2-containing NADPH oxidase in early ischemic preconditioning

Research output: Contribution to journalArticle

R M Bell, A C Cave, S Johar, D J Hearse, A M Shah, M J Shattock

Original languageEnglish
Pages (from-to)2037 - 2039
Number of pages3
JournalFaseb Journal
Volume19
Issue number14
DOIs
Publication statusPublished - Dec 2005

King's Authors

Abstract

Reactive oxygen species (ROS)-mediated signaling is implicated in early ischemic preconditioning ( PC). A NOX-2-containing NADPH oxidase is a recognized major source of ROS in cardiac myocytes, whose activity is augmented by preconditioning mimetics, such as angiotensin II. We hypothesized that this oxidase is an essential source of ROS in PC. Hearts from wild-type ( WT) and NOX-2 knockout ( KO) mice were Langendorff perfused and subjected to 35 min ischemia/reperfusion with or without preceding PC or drug treatment. Infarct size was measured by triphenyl tetrazolium chloride staining, and NADPH oxidase activity by lucigenin chemiluminescence. PC significantly attenuated infarct size in WT ( 26 +/- 2% vs. control, 38 +/- 2%, P <0.05) yet was ineffective in KO hearts ( 33 +/- 3% vs. control, 34 +/- 3%). Concomitantly, PC significantly increased NADPH oxidase activity in WT (+ 41 +/- 13%; P <0.05), but not in KO ( - 5 +/- 18%, P = NS). The ROS scavenger MPG (N-2-mercaptopropionyl glycine, 300 mu mol/ L) abrogated PC in WT ( 39 +/- 2% vs. control, 33 +/- 1%). CCPA ( 2-chloro N6 cyclopentyl adenosine, 200 nmol/L), a putative ROS-independent PC trigger, significantly attenuated infarct size in WT, MPG-treated WT and KO hearts ( 24 +/- 2, 23 +/- 1, and 20 +/- 3%, respectively, P <0.05). Furthermore, CCPA did not augment NADPH oxidase activity over control (+ 22 +/- 11%, P = NS). Inhibition of protein kinase C (PKC) with chelerythrine (CHE, 2 mu mol/ L) completely abrogated both PC ( 38 +/- 2% vs. CHE alone, 35 +/- 2%) and associated increases in oxidase activity (+ 3 +/- 10%, P = NS). PKC-dependent activation of a NOX-2-containing NADPH oxidase is pivotally involved in early ischemic PC. However, adenosine receptor activation can trigger a ROS and NOX-2 independent PC pathway

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